Search Results (90)

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder involving metabolic impairment, neuroinflammation, synaptic failure, and comorbidities. Hence, therapeutic development for AD is rapidly shifting from a single-target approach, centred on amyloid-beta (Aβ) reduction, to multi-target strategies. In this study, we investigated the neuroprotective profile of two acetanilide derivatives, SG-22 and SG-23, originated from the halogen-free thyronamine-like lead compound SG-2. Their efficacy was evaluated through an integrated approach combining in vitro cellular models, in vivo phenotypic screening in a Caenorhabditis elegans AD model, and comprehensive ADME-Tox profiling. In U87MG cells, both SG-22 and SG-23 effectively prevented Aβ_25–35-induced cytotoxicity and restored autophagy-related gene expression, including LC3, SIRT1, and SIRT6, while reducing mTOR and SIRT5 levels. Furthermore, all compounds exhibited anti-inflammatory effects in activated HMC3 microglial cells, reducing IL-6 and increasing IL-10 levels, with evidence suggesting partial involvement of TAAR1 signalling. ADME-Tox analyses revealed improved safety and metabolic profiles for the tested compounds, particularly SG-22, which showed reduced hERG liability and enhanced cytochrome P450 stability. However, in vivo studies demonstrated that only SG-2 and SG-23 improved motility and fitness in the C. elegans AD model, consistent with their ability to activate autophagy, whereas SG-22 was ineffective due to limited organismal uptake. Ultimately, the monoacetylated analogue SG-23 emerges as a promising candidate, balancing neuroprotective efficacy and drug-like properties, and supporting thyronamine-like analogues as multi-target agents for AD. Full article

The antitumoral activity of monoamine receptor ligands appears to be important as a potential approach to cancer medication. In the present study, we evaluated the effects of trace amine compounds, including octopamine, tyramine, 3-methoxytyramine, and synephrine, on SH-SY5Y neuroblastoma cells. Previously, these compounds exhibited TAAR1-specific activity at nanomolar concentrations. However, in SH-SY5Y neuroblastoma cells, the effect of octopamine and 3-methoxytyramine was identified in concentrations of 1000 µM or above and is apparently non-specific. Neither public transcriptomic datasets nor qPCR analysis detected significant TAAR1 expression in SH-SY5Y cells, suggesting that the observed effects may be mediated by adrenoceptors. Among these, ADRA2C was the most highly expressed in SH-SY5Y cells. Analysis of transcriptomic data from the GEO database revealed that adrenoceptors are widely expressed in neuroblastomas. The expression profiles of adrenoceptors in tumors are polymorphic and more complex than in SH-SY5Y cells. Thus, the effects of trace amines on other neuroblastoma cell lines and in vivo tumors warrant further investigation, and the involvement of adrenoceptors in this process may be speculated. Our findings suggest the non-specific activity of trace amines against tumor cells, with a paradoxical stimulatory effect in differentiated neuroblastoma cells, which highlights the need for caution in studies involving TAAR1-specific compounds. Full article

Acrylic resin is widely used in the fabrication of complete dentures, interacting significantly with the intraoral environment. However, complete dentures face challenges such as stability issues and biofilm accumulation. Glaze application is a common method to reduce surface porosity and microbial adhesion, but it also decreases surface wettability, potentially impairing salivary film formation essential for peripheral sealing. This study aimed to incorporate titanium dioxide and zinc oxide nanoparticles into the glaze applied to thermally activated acrylic resin (TAAR) via spray coating to enhance surface wettability and antifungal activity. Four groups were tested: G (TAAR + commercial glaze − control); AlG (TAAR + commercial glaze + aluminum oxide − roughness control); TiG (TAAR + commercial glaze + titanium dioxide); and ZnG (TAAR + commercial glaze + zinc oxide). Evaluations included flexural strength, color and translucency, surface analysis and antibiofilm activity against Candida albicans. Data were analyzed using one-way ANOVA. No statistically significant differences in mechanical strength (MPa) were observed (G: 108.54 ± 8.36; AlG: 113.60 ± 11.95; ZnG: 111.98 ± 9.27; TiG: 113.66 ± 10.41). Surface roughness significantly increased, and contact angle decreased, indicating improved wettability. Regardless of the antifungal activity no improvement was detected (G: 6.71 ± 0.10; AlG: 6.82 ± 0.08; ZnG: 6.72 ± 0.20; TiG: 6.66 ± 0.18). In conclusion, the incorporation of nanoparticles into the glaze improves the wettability of acrylic resin surfaces, potentially enhancing peripheral sealing and denture retention, which is beneficial for patients with reduced alveolar ridge height. Full article

Background: Spinal cord injury (SCI) is a severe pathological condition resulting in persistent motor and sensory impairments. The trace amine-associated receptor 5 (TAAR5) is a potential modulator of central nervous system functions; however, its role in CNS repair remains poorly understood. Methods: We comprehensively evaluated the effect of TAAR5 gene knockout on functional recovery following lateral spinal cord hemisection in TAAR5-KO and wild-type (WT) male mice. Sensorimotor recovery after SCI was assessed using the horizontal ladder, grasp, and hindlimb mobility tests. Exploratory and anxiety-like behaviors were evaluated using the open field and elevated plus maze tests before and 5 weeks after SCI. Results: TAAR5-KO mice exhibited accelerated recovery of sensorimotor functions, as assessed by joint mobility and grasping tests, compared to WT animals. In contrast, no significant intergroup differences were found in the Horizontal Regular Ladder test, likely due to the task complexity and an insufficient recovery period. Nevertheless, SCI induced elevated anxiety-like behavior regardless of genotype. Conclusions: These findings indicate that TAAR5 deficiency exerts a positive modulatory effect on the restoration of specific components of sensorimotor function after SCI. This effect may be mediated through the modulation of dopaminergic neurotransmission and inflammatory processes. The observed beneficial effect of TAAR5 knockout identifies this receptor as a promising target for developing novel therapeutic strategies aimed at improving functional outcomes following spinal cord injury. Full article

Olfaction is crucial for ducks, influencing essential behaviors such as foraging and mating. However, the molecular basis of sex-associated variation in duck olfactory tissues remains poorly understood. Here, we performed bulk RNA-seq on turbinate tissue from male and female Tianfu Nonghua Mottled Ducks (Anas platyrhynchos domesticus Linnaeus, 1758; Anatidae) to characterize sex-biased transcriptional programs. Our results suggest strong global transcriptomic separation between males and females, with 1906 differentially expressed genes (DEGs) identified. These DEGs were enriched in pathways related to neuronal signaling, cell adhesion, and extracellular matrix organization, suggesting coordinated sex-associated differences in signaling and tissue-organization programs. While olfactory receptor (OR) and trace amine-associated receptor (TAAR) genes showed limited sex-biased expression in bulk tissue, two neuromodulatory GPCRs, TACR2 and DRD4, were prioritized as hub genes within sex-biased co-expression networks. Notably, both genes also showed relatively high expression in turbinate tissue and neuroendocrine centers in an integrated multi-tissue transcriptomic dataset, nominating them as candidate targets for future functional and cell-type-resolved investigations. Overall, our study provides a descriptive molecular profile of sex-biased transcription in duck turbinate tissue, laying a foundation for follow-up studies and potential applications in poultry breeding and management. Full article

Recent studies indicated a connection between trace amine-associated receptor 5 (TAAR5) and emotional behaviors related to anxiety and depression; however, the neurobiological basis of this link is still unclear. Using mutant TAAR5 knockout (TAAR5-KO) mice, we explored the consequences of receptor deletion on dopamine (DA) dynamics in the ventral striatum and stress-related behaviors. Voltammetric measurements of DA in the nucleus accumbens (NAc) coupled with electrical stimulation of the ventral tegmental area (VTA) revealed that mice lacking TAAR5 display a greater DA release, while its reuptake is not affected. Behaviorally, mutants were significantly less anxious in the elevated plus maze (EPM) and consumed more sucrose in comparison with wild-type (WT) controls. The new object recognition test (NOR) did not uncover a difference between these genotypes. During predator (rat) stress exposure, mutant and WT mice showed quite distinct responses versus the behavior observed in stressless conditions. Control animals demonstrated a substantial increase in “freezing” (a sign of passive coping), while “running” and “exploring” patterns (signs of active coping) were significantly extended in mice lacking TAAR5. Short-term consequences of stress were explored 24 h following the predator exposure. The absence of TAAR5 did not prevent or reduce stress-induced anxiety in the EPM. In fact, the level of anxiety in mutants reached that observed in control mice. Furthermore, activity in NOR was significantly decreased in mice lacking TAAR5 but not in WT animals. On the other hand, predator exposure resulted in impaired NOR in the WT control, whereas mutants’ performance was not altered. These findings indicate that TAAR5 deletion leads to significant DA imbalance, which might at least partly explain the better stress-coping strategy and other stress-induced behavioral consequences observed in mutant animals. Full article

Background/Objectives: The therapeutic potential of selective trace amine-associated receptor 1 (TAAR1) agonists has been established in multiple animal models of depression and anxiety. PTSD is a debilitating psychiatric disorder frequently characterized by anxiety and often comorbid with major depressive disorder. Complex PTSD represents an even more severe clinical presentation, emerging from prolonged or repeated exposure to traumatic events. Recent studies indicate that TAAR1 agonists can attenuate anxiety-like behaviors in experimental models of PTSD; however, the molecular mechanisms underlying this effect remain poorly understood. In this study, we evaluated whether TAAR1 agonism modulates PTSD-related neurochemical and molecular changes within the hippocampus and striatum. Methods: Post-traumatic stress was modeled using predator stress, a validated experimental paradigm relevant to complex PTSD. Treatment consisted of intraperitoneal administration of the TAAR1 agonist LK00764. Monoamine neurotransmitters and their metabolites were quantified, and the expression of genes implicated in noradrenergic, dopaminergic, and serotonergic signaling pathways was assessed. In addition, gene network reconstruction was performed using artificial intelligence to identify TAAR1-dependent regulatory interactions. Results: Treatment with a TAAR1 agonist fully prevented behavioral abnormalities in the experimental model of complex PTSD. Neurochemical analyses revealed decreased 5-HT levels in the hippocampus and reduced dopamine and metabolite concentrations in the striatum following TAAR1 agonism. Moreover, TAAR1 activation was associated with increased expression of the neurotrophic factor BDNF in the striatum. Gene network reconstruction identified a distinct molecular hub within the PTSD network, comprising TAAR1-coexpressed genes, their encoded proteins, and interconnected signaling pathways, suggesting a tightly regulated feedback loop. Conclusions: These findings provide novel evidence that TAAR1 agonists exert protective effects against complex PTSD-related behavioral and neurochemical abnormalities. The reconstructed TAAR1-centered gene network offers mechanistic insight into receptor-dependent regulation of monoaminergic signaling and neuroplasticity, supporting further exploration of TAAR1 agonists as promising therapeutic candidates for PTSD. Full article

Background/Objectives: Family history is a known risk factor for multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Previous genome-wide association studies (GWASs) have identified 35 common loci associated with MM risk and 21 associated with MGUS. The objective of this study was to identify less common and rare genetic loci predisposing to MM/MGUS through whole-exome sequencing (WES)-based linkage analysis. Methods:Multipoint linkage analysis was conducted using the Multipoint Engine for Rapid Likelihood Inference (MERLIN) with the Lander–Green algorithm on germline WES data from 79 pedigrees with 2 or more affected relatives (120 MM, 86 MGUS, and 21 unaffected). Genome-wide linkage was evaluated using 12,946 independent single-nucleotide variants (linkage disequilibrium r² < 0.05). Results: Significant linkage was observed at chromosome 6q22.33–q24.2 by the non-parametric model (logarithm-of-odds (LOD) = 3.3) and suggestive linkage by the dominant parametric model (heterogeneity LOD (HLOD) = 2.5). Fourteen rare variants within this region were prioritized using family-specific partial LOD scores and in silico functional prediction tools. Nine of these variants, REPS1, THEMIS, TAAR6, AHI1, VNN1, VNN3, MTFR2/FAM54A, LAMA2, and PHACTR2, overlapped immune-regulatory regions in blood cell lines and were not previously identified in GWASs. Conclusions: This study demonstrates the utility of applying a linkage analysis framework to familial WES data for identifying genomic regions and candidate genes that may contribute to MM/MGUS predisposition. These findings provide new insight into the inherited risk and etiology of familial MM and MGUS. Full article

Mannitol dehydration is routinely used to prevent and treat cerebral damage after total aortic arch replacement (TAAR), but existing neuroimaging technologies cannot achieve bedside real-time quantitative assessment of its impact on cerebral perfusion in different patients. This study applied dynamic cerebral perfusion electrical impedance tomography (DCP-EIT), a non-invasive neuroimaging technique, for bedside cerebral perfusion monitoring in TAAR patients during dehydration. Seventeen patients with normal neurological function and nineteen with neurological dysfunction (ND) were enrolled. The variation patterns and differences in perfusion impedance, images, and the relative ratios (RY) of mean perfusion velocity (MV), height of systolic wave (Hs), inflow volume velocity (IV), and angle between the ascending branch and baseline (A_ab) were analyzed. Results showed DCP-EIT could visualize cerebral perfusion changes, with detected poorly perfused regions showing good consistency with ischemic areas identified by computed tomography (CT). RY of normal patients fluctuated around 0.97–1.04, with no significant difference from baseline. RY of ND patients peaked at 14–20 min after dehydration and remained higher than baseline even at 100 min (p < 0.001). DCP-EIT holds potential to optimize individualized cerebral protection strategies for other cerebral damage scenarios and neurocritical care. Full article

TAAR1 agonists have emerged as promising therapeutic agents capable of modulating glucose homeostasis, enhancing insulin secretion and suppressing appetite, making them attractive candidates for the treatment of obesity and related metabolic disorders. Despite their potential, the number of TAAR1-targeting compounds with well-defined pharmacological profiles remains limited. In this study, we identified and characterized JP-14, a novel aminoguanidine-based TAAR1 agonist, in a comprehensive panel of pharmacological assays. JP-14 promoted glucose uptake in HepG2 cells and reduced lipid deposition during 3T3-L1 adipocyte differentiation, with both actions dependent on TAAR1 signaling. In differentiated 3T3-L1 adipocytes, JP-14 reduced intracellular levels of both neutral lipids and phospholipids, indicating dual anti-steatotic and anti-phospholipidotic activity. In zebrafish larvae, toxicity profiling confirmed 10 µg/mL as a safe concentration for further in vivo studies. These assays showed that JP-14 promoted lipid mobilization and partially prevented fructose-induced lipid accumulation, demonstrating systemic metabolic benefits in vivo. Moreover, JP-14 markedly delayed gastric emptying in mice, an effect similar to loperamide and reversed by TAAR1 antagonism, supporting its role in regulating satiety and energy balance. Collectively, our findings establish JP-14 as a safe and metabolically active TAAR1 agonist with multifaceted effects on glucose and lipid metabolism. JP-14 represents a valuable pharmacological tool for probing TAAR1-mediated mechanisms in metabolic regulation. Full article

Human remains detection (HRD) dogs are vital tools in forensic science and disaster response, but their training is limited by the restricted availability of human material. Synthetic odorants such as Sigma Pseudo™ formulations provide safer, standardized alternatives, yet current products reproduce only a fraction of the volatile organic compound (VOC) profile of decomposition. In particular, sulfur-containing volatiles, which are highly odor-active and consistently present in human remains, are often missing, reducing biological fidelity. Here, we integrate analytical chemistry with canine olfactory genetics and molecular biology to explain these limitations. Dogs possess one of the largest olfactory receptor (OR) repertoires among mammals, with high allelic diversity and specialized trace amine-associated receptors (TAARs) tuned to cadaveric amines. Together with olfactory binding proteins (OBPs) and ciliary signal transduction cascades, these molecular mechanisms highlight why incomplete VOC mixtures may fail to activate the full receptor network required for reliable odor imprinting. We propose the “sulfur gap hypothesis” and suggest hybrid training strategies combining improved synthetics with ethically sourced biological samples to enhance HRD dog performance. Full article

Background/Objectives: Methamphetamine (METH), a potent psychostimulant, exerts harmful effects on the vascular system by promoting oxidative stress, inflammation, and endothelial injury. While its impact on the blood–brain barrier is well documented, its influence on the retinal microvasculature remains less understood. This study investigated the effects of METH on syndecan-1 expression and endothelial function in primary rat retinal microvascular endothelial cells (RRMECs) and isolated ophthalmic arteries. Methods: We assessed METH-induced changes in mRNA and protein expression levels of syndecan-1, matrix metalloproteinase (MMP)-2, and MMP-9. Endothelial function was evaluated using scratch migration assays and trans-endothelial electrical resistance (TEER) measurements. The mechanistic involvement of MMP-9 and trace amine-associated receptor 1 (TAAR-1), a known receptor for METH, was examined using selective pharmacological inhibitors. Results: METH exposure significantly decreased syndecan-1 expression and increased MMP-9 levels. These changes were accompanied by impaired endothelial migration and reduced TEER in RRMECs. Similar findings were confirmed in cultured ophthalmic arteries, reinforcing the translational relevance of our in vitro results. Inhibition of MMPs restored syndecan-1 expression and rescued endothelial function. Furthermore, TAAR-1 antagonism protected against syndecan-1 degradation, reduced MMP-9 upregulation, and improved endothelial migration and barrier resistance. Conclusions: Our findings suggest that METH induces loss of syndecan-1 and retinal vascular integrity by promoting TAAR-1–mediated MMP-9 upregulation. Targeting the TAAR-1/MMP-9 axis may offer a promising therapeutic strategy for preventing METH-induced microvascular damage in the retina. Full article

Background: Dopamine participates in the cognitive cerebellar role and in cerebellum development. The trace amine-associated receptor (TAARs, TAAR1-TAAR9) system contributes to dopamine signaling tuning. So, the aim of the present study is the analysis of the TAARs’ gene expression and functional associations in prenatal and neonatal mouse cerebellums. Methods: The transcriptomic data represented in the GEO repository was performed to identify Taars expression and co-expression patterns in embrionic and postnatal mouse cerebellum. Results: Open transcriptomic data analysis showed cerebellar expression of the Taar5 gene mRNA both in prenatal and early postnatal samples. The identified Taar5 expression was confirmed by RT-PCR in P5 mice. We identified the association between Taar5 expression and the expression of proliferation-related genes in late prenatal E13.5 samples, which was replaced by co-expression with genes involved in metabolism in P5–6 samples. These associations are suggested to mirror the previously identified Taar5 expression in Purkinje cells, which proliferate at the E13.5 and mature in the postnatal period. However, the analysis of TAAR5 co-expression with markers of different cell populations revealed the pronounced co-expression of TAAR5 in the P5–6 cerebellum with microglial markers, which is shifted to the association with astroglial markers in P10. Conclusions: The Taar5 gene was found to be active in the cerebellum samples taken around birth, and its co-expression pattern differs in the embryo stage and the early days after birth. We suggest that the Taar5 receptor may be involved in cerebellum development; however, further research is necessary to elucidate its role in this process. Full article

Background/Objectives: G protein-coupled trace amine-associated receptors (TAARs) belong to a family of biogenic amine-sensing receptors. TAAR1 is the best-investigated receptor of this family, and TAAR1 agonists are already being tested in clinical studies for the treatment of schizophrenia, anxiety, and depression. Meanwhile, other TAARs (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9 in humans) are mostly known for their olfactory function, sensing innate odors. At the same time, there is growing evidence that these receptors may also be involved in brain function. TAAR8 is the least studied TAAR family member, and currently, there is no data on its function in the mammalian central nervous system. Methods: We generated triple knockout (tTAAR8-KO) mice lacking all murine Taar8 isoforms (Taar8a, Taar8b, and Taar8c) using CRISPR-Cas9 technology. In this study, we performed the first phenotyping of tTAAR8-KO mice for behavioral, electrophysiological, and neurochemical characteristics. Results: During the study, we found a number of alterations specific to tTAAR8-KO mice compared to controls. tTAAR8-KO mice demonstrated better short-term memory, more depressive-like behavior, and higher body temperature. Also, we observed changes in the dopaminergic system, brain electrophysiological activity, and adult neurogenic functions in mice lacking Taar8 isoforms. Conclusions: Based on the data obtained, it can be assumed that the physiological TAAR8 role is not limited only to the innate olfactory function, as previously proposed. TAAR8 could be involved in brain function, in particular in dopamine function regulation. Full article

Background: Cefiderocol (CFD) is a novel siderophore cephalosporin developed for the treatment of infections involving multidrug-resistant (MDR) Gram-negative bacilli (GNB) infections (1–3). For bone and joint infections (BJIs), the use of CFD is currently neither part of its market authorization nor recommended, and has not yet been assessed by large-scale studies. Objectives: To fill the scarcity of data regarding the use of CFD in BJIs, we aimed to describe patients’ and infection characteristics along with the outcomes of the infection. Methods: We conducted a retrospective observational multicenter study in 22 French centers from January 2019 to December 2023. Results: From January 2019 to December 2023, 45 patients were included. Patients were mainly males (73%) with a median age of 62 years (interquartile range [IQR] 29), and a median Charlson comorbidity index of 3. Implant-related infections (20) were the most prominent, accounting for 44% of the cases. Carbapenemase-producing GNB were involved in 74% of the cases (n = 17/23), among which Pseudomonas aeruginosa accounted for 38% of these cases. Most patients received 6 g of CFD per day. CFD was used in combination with an antibiotic in 40 out of 45 cases (89%). The median duration of CFD treatment was 34 days. Seven patients (16%) experienced side effects, mainly gastro-intestinal disorders, including three (7%) who induced treatment cessation. Infection control included surgery in 37 (82%) patients. Failures and deaths occurred, respectively, in 22 (49%) and 10 (22%) cases. Conclusions: Our results suggest that CFD may be an alternative in MDR-GNB infections with limited therapeutic options. Full article